Amiodarone hydrochloride, a drug that is effective in the treatment of intractable cardiac arrhythmias, can cause potentially life- threatening pulmonary toxicity. The goal of the proposed research is to delineate the pathogenesis of pneumotoxicity by utilizing a model in two rat strains. +The Fischer rat develops pulmonary inflammation along with a drug-induced phospholipidosis and accumulation of large quantities of drug and metabolite in the lung. These rats will be compared to the Wistar rat, which does not develop inflammation and accumulates less drug, metabolite, and probably phospholipid in the lung. The role of direct drug toxicity will be analyzed ny increasing the drug dose in the Wistar rat and determining whether this results in increased pulmonary accumulation of drug, metabolite, or phospholipid and correlates with the induction of inflammation. In vitro studies will examine whether the metabolite N-desethylamiodarone is more toxic than the parent drug+ and whether the drug or metabolite is differentially toxic to fibroblasts, endothelial cells, and type II pneumocytes isolated from the two strains. +Drug up-take by endothelial cells and type II pneumocytes from the two strains will also be examined.+ The role of a drug-induced hypersensitivity reaction will be examined by determining whether there is evidence of a cell-mediated immune reaction as evinced by reversal of the T4/T8 ratio delayed-type hypersensitivity in vivo, and lymphocyte transformation or LMIF release in vitro in response to either amiodarone or the metabolite. To determine whether humoral responses might be involved, the presence of immunoglobulin and complement in lung tissue or lavage fluid will be investigated. In addition, the effect of thymectomy on the development of drug- induced inflammation will be studied. Because the drug-induced lysosomal lipid accumulation may affect macrophage and lymphocyte function that could exacerbate the inflammation, the effect of phospholipidosis on immune responsiveness, prostaglandin release, and phagocytosis and killing of bacteria will be examined.